The Enduring Challenge of Advanced HIV Infection

List of authors.
  • Nathan Ford, M.P.H., Ph.D.,
  • and Meg Doherty, M.D., Ph.D.


Until recently, progress in the fight against human immunodeficiency virus (HIV) infection was primarily measured in terms of the number of patients who were started on antiretroviral therapy (ART). Major efforts to increase access to ART in the low- and middle-income countries that are most affected by HIV infection began in 2000, and over the following 15 years, an estimated 8 million HIV-related deaths were averted. In countries with a high burden of disease, this decline translated into important increases in life expectancy.1

Notwithstanding these gains, the decrease in HIV-associated deaths appears to have plateaued in recent years. HIV still causes more than 1 million deaths per year worldwide and remains a leading cause of death and complications in sub-Saharan Africa.1 A key explanation for this enduring high mortality is that despite an evolution toward offering treatment earlier in the course of the disease,2 HIV continues to be identified in a substantial number of patients with advanced infection (which is defined by the World Health Organization [WHO] as a CD4+ count of fewer than 200 cells per cubic millimeter). A recent study of trends across 55 countries showed that more than a third (37%) of the patients who initiated ART in 2015 already had advanced HIV infection.3 Such patients are at high risk for death, even after starting ART (which can increase the inflammatory response), and the risk increases with a decreasing CD4+ count.3 A worrisome new trend that has been observed in countries with long-standing HIV treatment programs is an increase in the number of patients who present for care with advanced HIV infection after a period of treatment interruption.4

A report on the REALITY trial, published in this issue of the Journal, describes a prophylaxis package that was aimed at reducing the risk of death among patients who presented with advanced HIV infection in four African countries: Uganda, Zimbabwe, Malawi, and Kenya.5 The package, which includes fluconazole (100 mg daily for 12 weeks), azithromycin (5 days), albendazole (single dose), and a fixed-dose combination tablet of trimethoprim–sulfamethoxazole, isoniazid, and pyridoxine, is designed to provide protection against leading infectious causes of hospitalization and death — in particular, tuberculosis, cryptococcal infection, and severe bacterial infections6 — among patients with advanced HIV infection.

In this trial, at the 24-week cutoff for the primary outcome, patients who had started the enhanced-prophylaxis package at the time of ART initiation had a 27% lower rate of death than those who received standard prophylaxis with trimethoprim–sulfamethoxazole alone (8.9% vs. 12.2% by Kaplan–Meier analysis). The incidence of new cases of tuberculosis was significantly lower with enhanced prophylaxis than with standard prophylaxis (7.1% vs. 10.2%), as was the incidence of cryptococcal infection (1.0% vs. 2.6%), candidiasis (1.1% vs. 2.6%), and new hospitalization (17.0% vs. 20.7%). The package of drugs had an acceptable side-effect profile; the levels of adherence were high, and there was no discernable effect on adherence to ART, despite the additional pill burden. Although the investigators did not find a between-group difference in mortality due to severe bacterial infections, it is plausible that a proportion of the unexplained causes of death (which made up 40% of all deaths and were significantly less common in the enhanced-prophylaxis group) included bacterial infections that are more challenging to diagnose with certainty.

This prophylaxis package is particularly relevant in centers with limited access to laboratory investigations such as cryptococcal antigen testing, tuberculosis diagnostics, and bacterial culture. In such locations, this approach is practical for reducing illness and death from the most common causes, which can occur rapidly. (Most of the deaths in the REALITY trial occurred within the first 3 weeks after ART initiation.) Nevertheless, there are some concerns with this approach that merit careful assessment — notably, the potential risk of microbial resistance to fluconazole and azithromycin and the cost-effectiveness of blanket prophylaxis in locations in which diagnostic tests are available. These issues were taken into consideration during a recent consultation held by the WHO to define a minimum package of diagnostic, prophylactic, and therapeutic interventions that should be made available to support the management of advanced HIV infection within a public health framework.7

In the REALITY trial, almost half the patients with a CD4+ count of fewer than 100 cells per cubic millimeter (the cutoff value for participation in the trial) had mild or no symptoms (WHO clinical stage 1 or 2 disease). This observation serves to highlight the limits of relying on clinical assessment alone to identify HIV-positive patients at high risk for severe disease and death. It also reinforces the importance of maintaining the capacity to measure CD4+ cells. In locations in which viral-load testing is available, the CD4+ count is no longer required in order to determine a patient’s eligibility for antiretroviral therapy or to track the response to treatment, yet measurement of the CD4+ count remains essential for assessing the risk of severe disease, both in patients who newly present for care and in those who return for care after a period of treatment interruption.8

With the advent of new treatment options, HIV infection has evolved from a probable death sentence to a chronic disease. If patients start ART early, they can expect a near-normal life expectancy.9 Early treatment also reduces the risk of HIV transmission,10 and much of the focus today is on reducing the spread of new infections to achieve epidemic control. Nevertheless, the relatively consistent proportion of patients who newly present for care with a low CD4+ count, together with an additional number of seriously ill patients who return for care after a period of treatment interruption, calls for a renewed focus to respond to the needs of patients with advanced HIV infection who are at high risk for illness and death.

Funding and Disclosures

Disclosure forms provided by the authors are available with the full text of this editorial at NEJM.org.

Author Affiliations

From the Department of HIV/AIDS, World Health Organization, Geneva.

Supplementary Material

References (10)

  1. 1. Global health sector response to HIV, 2000-2015: focus on innovations in Africa. Geneva: World Health Organization, 2015.

  2. 2. Eholié SP, Badje A, Kouame GM, et al. Antiretroviral treatment regardless of CD4 count: the universal answer to a contextual question. AIDS Res Ther 2016;13:27-27

  3. 3. Anderegg N, Kirk O. Immunodeficiency at the start of combination antiretroviral therapy in low-middle and high-income countries. Presented at the 21st International Workshop on HIV and Hepatitis Observational Databases. Lisbon, March 30–April 1, 2017. abstract.

  4. 4. Meintjes G, Kerkhoff AD, Burton R, et al. HIV-related medical admissions to a South African district hospital remain frequent despite effective antiretroviral therapy scale-up. Medicine (Baltimore) 2015;94:e2269-e2269

  5. 5. Hakim J, Musiime V, Szubert AJ, et al. Enhanced prophylaxis plus antiretroviral therapy for advanced HIV infection in Africa. N Engl J Med 2017;377:233-245

  6. 6. Ford N, Shubber Z, Meintjes G, et al. Causes of hospital admission among people living with HIV worldwide: a systematic review and meta-analysis. Lancet HIV 2015;2:e438-e444

  7. 7. Guideline for managing advanced HIV disease and the timing for initiating antiretroviral therapy: supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Geneva: World Health Organization, 2017.

  8. 8. Ford N, Meintjes G, Vitoria M, Greene G, Chiller T. The evolving role of CD4 cell counts in HIV care. Curr Opin HIV AIDS 2017;12:123-128

  9. 9. Antiretroviral Therapy Cohort Collaboration. Survival of HIV-positive patients starting antiretroviral therapy between 1996 and 2013: a collaborative analysis of cohort studies. Lancet HIV 2017 May 10 (Epub ahead of print)

  10. 10. Cohen MS, Chen YQ, McCauley M, et al. Antiretroviral therapy for the prevention of HIV-1 transmission. N Engl J Med 2016;375:830-839

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